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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Hydroxyeicosatetraenoic Acids on Furosemide-Sensitive Chloride Secretion in Rat Distal Colon

Markus Wegmann, Antje Kämpen, Susanne Weber, Hannsjörg W. Seyberth and Arnold Köckerling
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 133-138;
Markus Wegmann
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Antje Kämpen
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Susanne Weber
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Hannsjörg W. Seyberth
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Arnold Köckerling
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Abstract

Arachidonic acid metabolites such as prostaglandins, thromboxanes, and leukotrienes are well known modulators of intestinal vascular perfusion, motility, and electrogenic ion transport. We investigated the effect of different hydroxyeicosatetraenoic acids (HETEs) from cytochrome P450- and lipoxygenase-dependent arachidonate metabolism on electrogenic chloride secretion in rat distal colon. Using conventional Ussing techniques, basolateral 12-HETE significantly decreased basal short-circuit current (Isc) and inhibited furosemide-sensitive Cl− secretion stimulated by either dibutyryl cAMP, prostaglandin E2, or theophylline in a concentration-dependent manner (IC50 = 1.5 nM). These data were underlined by significant inhibition of JnetCl in unidirectional 36Cl flux measurements. Direct regulation of the basolateral Na+-K+-2Cl− cotransporter or the Na-K-ATPase could be excluded because 12-HETE had no effect on furosemide-sensitive K+ secretion induced by epinephrine, or ouabain-sensitive Na+ reabsorption stimulated by aldosterone. Inhibitors of Ca2+-activated and voltage-gated K+ channels such as apamin, charybdotoxin, and dendrotoxin did not affect secretagogue-dependent Isc and its regulation by 12-HETE. In contrast, glibenclamide significantly attenuated the effect of 12-HETE on secretagogue-induced Isc, whereas chromanol 293B, an inhibitor of cAMP-dependent K+ conductance, had an additive effect. We speculate that 12-HETE, like glibenclamide, affects intestinal Cl−secretion by inhibiting basolateral K+ATPchannels. In contrast to these findings, neither 5-HETE nor 20-HETE had any effect on basal Isc or cAMP-dependent Cl−secretion.

Footnotes

  • Send reprint requests to: Dr. Markus Wegmann, Department of Pediatrics, Philipps University Marburg, Deutschhausstr. 12, D-35037 Marburg, Germany. E-mail:wegmannm{at}mailer.uni-marburg.de

  • ↵1 This study was supported by grants from Deutsche Forschungsgemeinschaft (Ko 1642/1-1) and Stiftung P.E. Kempkes, Marburg (Kz. 26/93).

  • Abbreviations:
    AA
    arachidonic acid
    CYP450
    cytochrome P450
    HETE
    hydroxyeicosatetraenoic acid
    VTE
    transepithelial voltage
    ΔVTE
    voltage deflections
    RTE
    total tissue resistance
    Isc
    short-circuit current
    DBcAMP
    dibutyryl cAMP
    PGE2
    prostaglandin E2
    ‰
    per thousand
    JnetCl
    net chloride flux
    mTAL
    medullary thick ascending limb
    • Received April 7, 2000.
    • Accepted June 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Hydroxyeicosatetraenoic Acids on Furosemide-Sensitive Chloride Secretion in Rat Distal Colon

Markus Wegmann, Antje Kämpen, Susanne Weber, Hannsjörg W. Seyberth and Arnold Köckerling
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 133-138;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Effect of Hydroxyeicosatetraenoic Acids on Furosemide-Sensitive Chloride Secretion in Rat Distal Colon

Markus Wegmann, Antje Kämpen, Susanne Weber, Hannsjörg W. Seyberth and Arnold Köckerling
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 133-138;
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